ABSTRACT The rapid development of the human brain in the first years of life determines critical brain-behavior relationships that are likely to set the stage for future clinical and functional outcomes. In parallel, infant behavioral studies show that high levels of negative emotionality (NE), low positive emotionality (PE), and emotional dysregulation are early risk factors for subsequent child behavioral and emotional problems. Emerging research also indicates a critical role of caregiving in shaping early brain-behavior relationships. Yet, little is known about the interface between functioning and structure in neural circuitries underlying emotional reactivity and early emotional regulation, the behavioral manifestations of these circuitries, and the ways in which caregiving quality might influence this neurobehavioral development. Our preliminary data (R21MH106570) show significant links between compromised white matter and intrinsic (resting state) functional connectivity in prefrontal cortical-subcortical emotional reactivity/ regulation circuitry in 3-month infants and independent observations of: 1) high NE relative to PE assessed concurrently; and 2) emotional dysregulation assessed 6 months later. We have also shown that insensitive maternal behavior at 3 months is associated with disrupted relationships between infant brain structure and intrinsic functional connectivity, and NE and PE. We now propose a larger-scale, longitudinal study of 120 infants, which will examine the predictive utility of infant brain structure and intrinsic functional connectivity at 3 and 9 months, and changes between 3 and 9 months, on trajectories of NE, PE and emotional regulation from 3 to 18 months, and the impact of caregiving on these developing brain-behavior relationships. Infants will be sampled across the spectrum of risk for emotionality and emotional dysregulation, as a function of caregiver report of emotional instability in the postpartum period. Infants will undergo MRI scans during sleep at 3 and 9 months. PE, NE and emotional regulation will be measured at 3, 9 and 18 months, via primary caregiver reports and independent observations. Caregiving behavior will also be assessed in separate sessions with the infant at 3, 9 and 18 months. We aim to examine: 1) prospective relationships among neural circuitry structure and intrinsic functional connectivity at 3 and 9 months, and change from 3 to 9 months, and: 3-18 month changes in emotional reactivity and regulation; and 2) the influence of caregiving on these brain-behavior relationships across the first 18 months of life. Exploratory analyses will also explore the effect of the sex of the infant upon infant brain-behavior relationships. Elucidating these brain-behavior relationships early in life will help identify objective neural markers among at-risk children before clinical problems emerge, and provide targets for new interventions to improve the health and well-being of children at risk for future psychopathology.